1. Field of the Art
The present invention relates to the production of aziridine-2-carboxylic acid salts, more particularly to (1) the synthesis of aziridine-2-carboxylic acid salts, particularly calcium or barium salt, and (2) the recovery of the aziridine-2-carboxylic acid salts according particularly to a liquid chromatography.
The aziridine-2-carboxylic acid salts themselves and their derivatives have physiological activities such as antineoplastic activities, and they are useful as intermediates or starting materials for .alpha.-amino acids such as serine, medicines, pesticides and functional resins.
2. Prior Art and Problems
For the synthesis of metal salts of aziridine-2-carboxylic acid, the following processes have been known:
(1) a process wherein a 2,3-dibromopropionic acid ester is reacted with liquid ammonia, and the resulting aziridine-2-carboxylic acid ester is reacted with an alkali metal or alkaline earth metal hydroxide in water to form a salt of aziridine-2-carboxylic acid [E. Kyburz et al., Helv. Chim. Acta 49 (1), 359 (1966) and K. D. Gundermann et al., Chem. Ber. 93, 1632 (1960)];
(2) a process wherein an .alpha.-halo-.beta.-aminopropionitrile or its mineral acid salt is reacted with an alkali metal or alkaline earth metal hydroxide in water or a hydrous organic solvent to form an aziridine-2-carboxylic acid salt (see the specification of Japanese Patent Laid-Open No. 83470/1981); and
(3) a process wherein a 2,3-dihalopropionitrile or .alpha.-haloacrylonitrile is reacted with ammonia in water or a hydrous organic solvent to form an .alpha.-halo-.beta.-aminopropionitrile which is then reacted with an alkali metal or alkaline earth metal hydroxide without isolation of the .alpha.-halo-.beta.-aminopropionitrile to form a salt of aziridine-2-carboxylic acid (see the specifications of Japanese Patent Laid-Open Nos. 90055/1981 and 100759/1981).
Though the above-mentioned processes are valuable, they still have some problems. That is, the process (1) is industrially disadvantageous since the yield of the aziridine-2-carboxylic ester is low, and the recovery of this compound in a step of purification by distillation is also low because the aziridine-2-carboxylic acid ester per se is unstable. The process (2) cannot be recommended from an industrial viewpoint since the .alpha.-halo-.beta.-aminopropionitrile is unstable. For handling this compound stably, it should be converted into a mineral acid salt thereof by quite complicated steps. Although the drawbacks of the process (2) are overcome to some extent by the process (3), the formed, unstable .alpha.-halo-.beta.-aminopropionitrile must be reacted immediately with an alkali metal or alkaline earth metal hydroxide. The requirements of this treatment are insufficient from the industrial viewpoint.
Thus, it cannot be considered that the processes for the production of the aziridine-2-carboxylic acid salts on an industrial scale have been completely developed.
On the other hand, for the recovery of the aziridine-2-carboxylic acid salts, the following processes wherein an aziridine-2-carboxylic acid ester obtained by reacting a 2,3-dibromopropionic acid ester with ammonia is used have been known:
(1) a process wherein: an aqueous lithium hydroxide solution is added to a solution of ethyl aziridine-2-carboxylate in ethanol to carry out the reaction in a cold place; the reaction product is dried under reduced pressure to obtain a syrup; then benzene is added to the syrup; the mixture is subjected to an azeotropic distillation to remove residual water; anhydrous ethanol is added thereto; and lithium aziridine-2-carboxylate thus precipitated is recovered [the above-mentioned Chem. Ber. 93, 1632 (1960)].
(2) a process wherein: a solution of metallic sodium in a mixture of ethanol and ether is added to a solution of isopropyl aziridine-2-carboxylate; the mixture is stirred together with a small amount of water to form sodium aziridine-2-carboxylate precipitate; and this precipitate is recovered [the above-mentioned Helv. Chim. Acta., 49, 359 (1966)].
These processes have a problem in that the yield of the starting aziridine-2-carboxylic acid ester itself is poor and that the recovery of the product ester in the step of the purification by distillation or the like is also poor since the aziridine-2-carboxylic acid ester per se is unstable. Further, for the recovery of solid aziridine-2-carboxylic acid salts from its solution, an industrially satisfactory process has not yet been developed. Since complicated treatments such as concentration to dryness under reduced pressure, azeotropic distillation, addition of a precipitating agent such as ethanol or ether and recovery by filtration are necessitated, the recovery of the aziridine-2-carboxylic acid salt is poor, and repurification is necessary for obtaining a highly pure product because such a compound having a high hygroscopicity as sodium aziridine-2-carboxylate frequently contains impurities.
Although several industrially advantageous processes for the production of aziridine-2-carboxylic acid salts have been proposed (see, for example, the specifications of the above-mentioned Japanese Patent Laid-Open Nos. 90055/1981 and 100759/1981), the reaction liquid obtained by these processes contains a large amount of an inorganic salt in addition to the aziridine-2-carboxylic acid salt. The presence of such an impurity is undesirable when the aziridine-2-carboxylic acid salt thus obtained is used directly as a starting material for medicines, pesticides or serine for which they have been used mainly heretofore. Particularly, the presence of a halogen ion reduces the yield of the intended product seriously when, for example, serine is to be produced from the aziridine-2-carboxylic acid salt. However, the highly pure aziridine-2-carboxylic acid salt cannot be obtained from an aqueous solution thereof containing the inorganic salt by the known recovering processes.
In our experiments wherein ethanol used as a precipitating agent was added to an aqueous solution containing an aziridine-2-carboxylic acid salt, an inorganic salt and other impurities, the formed precipitate contained the inorganic salt in addition to the aziridine-2-carboxylic acid salt, and, therefore, this process could not be employed as an effective process for recovering highly pure aziridine-2-carboxylic acid salt (see Comparative Example B2 given below).
Therefore, for obtaining aziridine-2-carboxylic acid salts of high purity, the use of the following process wherein an inorganic salt is substantially not by-produced in the production of the aziridine-2-carboxylic acid has been unavoidable.
(3) a process wherein triethanolamine is added to a solution of ethyl .alpha.-chloro-.beta.-aminopropionate hydrochloride in ethanol to precipitate triethanolamine hydrochloride; this precipitate is filtered out; an aqueous lithium hydroxide solution is added to the filtrate to carry out the reaction in a cold, dark place for 24 h; the reaction mixture is concentrated to dryness under reduced pressure to obtain a syrup; benzene is added to the syrup; water remaining therein is removed by an azeotropic distillation; ethanol and ether are added thereto; and the thus formed lithium aziridine-2-carboxylate is recovered (see "process for the synthesis of the standard" given in the specification of the above-mentioned Japanese Patent Laid-OPen No. 83470/1981).
Thus, a practicable technique has not yet been developed, although the development of a process for recovering the quite useful aziridine-2-carboxylic acid salts by the separation from inorganic salts and other impurities efficiently in an industrially advantageous manner has been eagerly sought.